OVERVIEW: What every practitioner needs to know

Are you sure your patient has pancreatic islet cell tumors? What are the typical findings for this disease?

Pancreatic islet cell tumors, also referred to as pancreatic neuroendocrine tumors (PNETs), are incredibly rare and difficult to diagnose unless one has a high index of suspicion and an excellent understanding of the presenting symptoms. Furthermore, diagnosis of these tumors must include correlation of historical facts, physical findings, laboratory testing and radiographic imaging. Finally, surgery plays a key role in the treatment of these neoplasms.

The most common symptoms depend on the specific tumor identified and the hormone that is overproduced.

If an insulinoma, then lethargy, fatigue, mental status changes (symptoms of hypoglycemia).

If somatostatinoma, then diarrhea, and symptoms related to cholelithiasis and diabetes mellitus.

What other disease/condition shares some of these symptoms?

Peptic ulcer disease

Anemia

Gallbladder conditions (cholecystitis, cholodocholithiasis)

Gastroenteritis (viral or bacterial)

Hepatitis

Appendicitis

Gastroesophageal reflux disease

Inflammatory bowel disease

Pancreatitis

What caused this disease to develop at this time?

There are no known or predisposing factors save a genetic predisposition as an inherited component of the Multiple Endocrine Neoplasia type I (MEN I) syndrome. MEN I is an autosomal dominant disorder with the offending gene on chromosome 11q13 (tumor suppressor).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

If an insulinoma, then there should be hypoglycemia in the presence of elevated insulin, proinsulin, and C-peptide levels. Elevated insulin levels in the absence of elevated proinsulin or C-peptide levels suggests surreptitious insulin administration.

If a glucagonoma, then there should be an elevated glucagon level.

If a gastrinoma, then there should be an elevated gastrin level in the presence of acid hypersecretion.

If VIPoma (vasoactive intestinal polypeptide), then there should be an elevated VIP level, in addition to severe hypokalemia and hypo-or achlorhydria.

If somatostatinoma, then there should be an elevated somatostatin level.

Would imaging studies be helpful? If so, which ones?

Plain radiographs to determine if obstruction or free-air suggestive of a hollow-viscus perforation (inexpensive, non-specific). (Order for any abdominal symptoms.)

Ultrasonography (US) - user-dependent and pancreas can be difficult to image completely or thoroughly. However, it still ranks as a critical first test and discussions should be held with the treating radiologist in order to alert him/her of the need for a thorough evaluation of the pancreas if possible. Secondary features, such as the presence of biliary pathology, liver abnormalities (lesions, tumors, etc.,), or other abdominal processes (other masses, abscess, fluid collections, acute inflammatory conditions [e.g., appendicitis]) will also be achieved. Order for any abdominal symptoms, especially in the presence of normal abdominal radiographs.

Axial imaging (MR [preferred because it involves no radiation exposure] or CT) - expensive and may require sedation for an adequate study in younger children, risk of contrast reactions, or radiation exposure. Order for the persistence of symptoms, in the presence of a mass found in the pancreas, liver, lesser sac on US, or, if symptoms persist and further radiologic investigation is warranted.

Nuclear medicine studies to specifically target and localize disease present (somatostatin-receptor scintigraphy [Octreoscan] or PET) - require specialized equipment and significant radiation exposure. Order to corroborate findings on the axial imaging or to look for the presence of metastases.

Endoscopy with endoscopic ultrasound (EUS) and/or endoscopic retrograde cholangiopancreatography (ERCP) (with possible tissue biopsy if anatomically feasible and a mass is identified) - localization, characterization and biopsy of the tumor/mass. Order to corroborate findings on the axial imaging.

Angiography - specialized capabilities required, radiation exposure, sedation/anesthesia, procedural complications. Order if symptoms persist and NO radiological correlate is defined on the previously described axial studies.

Confirming the diagnosis

There are no uniformly accepted algorithms available.

Specific symptoms produced by hormone excess are determined based on history, physical exam and lab findings. Radiologic studies are then used to define the exact location of the tumor, so that operative planning can be undertaken and executed.

If you are able to confirm that the patient has pancreatic islet cell tumors, what treatment should be initiated?

Patient stabilization and control of hormone excess (e.g., ensuring euglycemia in the presence of an insulinoma) is critical. Maintenance of normal homeostatic physiologic mechanisms are important, including maintenance of euvolemia, correction of electrolyte abnormalities, and minimization of organ dysfunction.

Surgery offers the only potential for a cure. Definitive treatment will be extirpation (complete) of the tumor that is metabolically active. It is often difficult to determine benign from malignant variants, but the goal of surgery should be complete removal of the tumor from the pancreas. This may require tumor enucleation or more formal pancreatic resections (splenic-preserving distal pancreatectomy, pancreaticduodenectomy).

Treatment of metastatic disease to the liver (primarily) as defined by radiologic studies may entail resection of these sites and/or ablative approaches (radio-frequency ablation (RFA), transarterial chemoembolization [TACE], radioembolization, microwave coagulation, or cryoablation) depending on the location and number of metastases involved. Orthotopic liver transplantation has also been employed to treat liver metastases with mixed results. Treatment of metastatic sites without control of the primary lesion or tumor may be undertaken in certain circumstances where benefit from tumor debulking (and hence decreased symptoms from hormone overproduction) may be warranted.

Medical treatment will vary with the precise etiology, location and quantity of disease, symptoms present and the nature of the disease (progressive disease, stable disease, etc.). Cytotoxic chemotherapy (streptozocin, oxaliplatin, temozolomide, etc.,), radioablative medical analogs (octreotide moieties), and molecular inhibitors (mTOR inhibitors, tyrosine kinase inhibitors, angiogenesis inhibitors) have all been used to treat these disorders. Precise regimens vary and depend on the nature of the patient's disease and symptoms present. Generally, these therapies are employed only for metastatic disease and for disease that is not amenable to surgical removal.

What are the adverse effects associated with each treatment option?

Significant morbidities exist with surgery, including the risks of postoperative complications from bowel obstruction to injury to surrounding organs. Postoperative recovery may require up to 7-10-day hospital stay with a 4-6-week recovery period. The precise risk varies for each procedure, but infection, bleeding and scar formation are certainly known risks for all. The majority of encountered or expected complications should be rare with a postoperative bowel obstruction being the most common.

Complications from treatment to metastatic sites will vary with the method employed and the nature of each procedure. Liver dysfunction (temporary), and/or hemorrhage are possible expectations from the treatments entertained to treat metastatic disease. The complications and outcomes for a liver transplantation in this setting are beyond the scope of this chapter and entail detailed discussions about patient selection, type of graft chosen, immunosuppressive regimen selected post-transplant, etc.

Cytotoxic, molecular and radioactive analogues will be expected to produce specific side-effects depending on the drug, dose, and regimen employed. Furthermore, for multiagent regimens, the side-effect profile of each drug may overlap, so careful monitoring is warranted.

What are the possible outcomes of pancreatic islet cell tumors?

The outcome of these diseases depend on the quantity and location of the tumor. For localized disease, complete extirpation should be curative with no need for adjuvant therapy. Monitoring for recurrence using a combination of radiographic and laboratory studies are warranted for the first 3-5 years after surgery.

Metastatic disease may be cured with complete resection or ablative therapies, but success depends on the size, number and location of the lesions involved. A more likely outcome is treating the disease as a chronic condition with utilization of therapies as symptom control for preservation of quality of life. With evidence of metastases, any of these tumors may produce chronic symptoms. If the disease cannot be treated using multimodality measures, death is the eventual outcome.

What causes this disease and how frequent is it?

These tumors are exceedingly rare in adults (0.4 per 100,000 population for insulinoma, the most common pancreatic islet cell tumor), and even more rare in children. Precise epidemiologic variables for children are not reported with any known accuracy, but a combined review of all pancreatic lesions reported in children in the 6 known reported series of 155 total pancreatic lesions demonstrated 36 tumors (23% of the total reported).

These tumors are known to be associated with the MEN 1 syndrome, occurring in a reported 20-70% of individuals with this condition.

How do these pathogens/genes/exposures cause the disease?

The MEN I gene is a tumor suppressor with the dysregulation of the gene product called menin (11q13). It is inherited in an autosomal dominant fashion, but not all cases of MEN I are attributed to this pathway and research is ongoing to determine other involved proteins or pathways.

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

N/A

Are additional laboratory studies available; even some that are not widely available?

N/A

How can pancreatic islet cell tumors be prevented?

No preventative factors are known.

Ongoing controversies regarding etiology, diagnosis, treatment

The single best adjuvant regimen(s) to treat metastatic disease, including chemotherapy and radiotherapy, are not universally accepted or known. Consultation with an oncologist well versed in these rare tumors, especially in regards to the burden of disease present and other medical comorbidities, is warranted prior to initiation of other adjuvant therapies.

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